The objective of the proposal is the design of newer classes and combination of antileprosy drugs which act more rapidly that the sulfones or phenazines and exert a mycobactericidal effect resulting in sterilization of tissues infected with Mycobacterium leprae. It is proposed to derive structure-activity data from specific enzyme target sites and growth inhibition studies with antifolates, antipolymerases and antimycobactins against low temperature myobacterial species used as models for the noncultivable leprosy bacillus. Thus a rational basis is available for testing candidate drugs against M. leprae in the mouse foot pad.